Aminopyridazone compounds and their



AMINOPYRIDAZONE COMPOUNDS AND THE MANUFACTURE Jean Druey, Riehen, and Konrad Meier and Alexander Staehelin, Basel, Switzerland, assignors to Ciba Pharmaceutical Products, Inc., Summit, N. J.

No Drawing. Application April 26, 1955, Serial No. 504,122

priority, application Switzerland April 29, 1954 6 Claims. or. 260-250) I This invention relates to aminopyridazone-(6) com pounds of the formula Ha I N-Rr

in which R1 indicates a phenyl radical, R2 is a hydroxyl group etherified with a lower aliphatic radical, and R3 stands for an amino radical substituted by at least one lower aliphatic radical.

More particularly, the invention relates to compounds of the above formula in which R is phenyl, R2 is a lower alkoxy group, such as a methoxy, ethoxy or propoxy group','and R3 is a lower monoalkylamino or dialkylamino group, in which the alkyl radicals are, for example, methyl, ethyl or propyl. Such compounds are designated herein as l-phenyl-3-lower alkoxy-M-lower monoalkyl aminoor lower dialkylamino-pyridazone-t6) compounds, wherein M stands for one of the positions 4 and 5.

1 The invention is especially concerned with 1-phenyl-3- methoxyl-dimethylamino-pyridazonee(6) of the formula (|)CHB and 1-phenyl 3-methoxy -dimethylamino-pyridazone-(6) thereto hereinabove, and Hal represents a halogen atom, for example, chlorine or bromine, is reacted with a lower aliphatic alcohol preferably in the form of an alcoholate. According to an alternative process, corresponding 3-hydroxyl compounds are converted into their ethers with lower aliphatic alcohols, for example, by reaction with reactive esters of the alcohols, especially esters with strong inorganic or organic acids, fdfexample, sulfuric acid or hydrohalic acids, preferablyin the presence of acid-binding agents, primarily such as are capable of alcoholate formation.

TV, J The new compoundscan also be prepared by reacting a compound of the formula j Hal N-Ri

in which R1, R2 and Hal have the same meaning as assigned thereto hereinabove, is reacted with a lower aliphatic primary or secondary amine.

The above reactions are carried out, for example, in the presence or absence of diluents and/or condensing agents and/or catalysts, at ordinary or elevated temperain which R1" and R3 have the same meaning as assigned A ture, in open vessels or in closed vessels under pressure.

The new compounds are utilized, for example," in the form of pharmaceutical preparations which contain them in admixture with an adjuvant which facilitates the administration thereof, such as'phermaceutical organicor inorganic carrier materials suitable for enteral or parenteral application. As carriers such substances are em ployed as do not react with the new compounds, as for example gelatine, lactose, starch, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, petroleum jelly, cholesterol or other known medicament carriers. The pharmaceutical preparation can be made up, for example, as tablets, dragees, or in liquid form as solutions, suspensions or emulsions. They may,

, if.desired,.- be-sterilized and/or contain auxiliary substances, such as preservative, stabilizing, wettingor emulsifying agents, salts for variation of the osmotic pressure or bufler substances. They can also contain other substances of therapeutic value. The preparations are formulated by customary methods employed in pharmaceutical formulation. i

The following examples illustrate the invention, the relation between'parts by weight and parts by volume being the same as that between the gram and the cubic centimeter.

- Example 1 0.4 part by weight of sodium is dissolved in 40 parts by volume of methanol and to the solution are added 4 partsby weight of 1-phenyl-3-chloro-4-dimethylaminopyridazone-( 6). The mixture is heated under reflux for 3 hours on the water bath. The methanol is then distilled ofit, the residue treated with water and extracted by 'shoking with chloroform. The dried organic solution-is evaporated, the residue dissolved in hot benzene and the solution filtered through animal charcoal. After the, addition of petroleum ether, the l-phenyl-3-methoxy-4-dimethylamino-pyridazone-(6) of the formula ,1

zO l 1;

crystallizes in white needles of M. P. IDS-101 C. The yield is 82%.

The l-phenyl-3-chloro-4-dimethylamino-pyridazone-(6 used as starting material can be prepared as follows: 7 400 parts byweight of chloromaleic acid anhydride are .boiled for three hours under reflux with 311 parts by volume of phenyl hydrazine and 2200 parts by volume of glacialacetic acid. After 15 hours standing'a't' ZO -C Z, the precipitate is filtered off and washed with glacial 'acetic acid. It is purified by dissolving in dilute causticsoda solution, filtering and precipitating with dilute hydroa eas-ea chloric acid and crystallized from glacial acetic acid. The "1 phenyl 3 hydroxy 4' chloro pyridazone (6) thus obtained melts with decomposition at 270 C.

85 parts by weight of this compound are heated for one hour to 100- C. with 680 parts by volume of phosphorus oxychloride. The solution is decomposed with ice-cold dilute caustic soda solution and extracted with ether. After drying over potassium carbonate, the ether is evaporated and the residue recrystallized from cyclohexane. The resulting 1-phenyl-3,4-dichloro-pyridazone- (6) melts at 138 C.

30 parts by weight of 1-phenyl-3,4-dichloro-pyridazone- (6) are suspended in 90 parts by volume of absolute alcohol and mixed with 52.5 parts by volume of 7 bl-alcoa holic d-inret-hylamine solution. The temperature rises to 60 C. After the reaction has subsided, the mixture is heated on the water-bath until dissolution is complete, then filtered warm and allowed to stand overnight at C. The crystallized 1-phenyl-3-chloro-4-dimethylamino-pyri'dazon e-(6) is recrystallized once again from alcohol. Melting point: 127128 C; Yield: 84%.

Example. 2

12.5 parts by weight of 1phenyl-3-chloro-5-dimethyl-amino-pyrida-zone-(6) are heated in a closed vessel with a solution of 1.2 parts by weight of sodium in 100 parts by volume of absolute methanol for 10 hours to 120-130 C. The product is filtered, the methanol distilled 01f, the residue taken up in ether and the ether solution, after washing with water, dried and evaporated. The remaining viscous oil is distilled under high vacuum. (Boiling point 133-135 C. under 0.03 mm. mercury pressure.) The yield is 94%. The distillate which becomes slowly permeated by crystals, is recrystallized from acetone petroleum other. There is thus obtained the l-phenyl- 3-methoxy-5-dimethylamino-pyridazone-(6) of the for mula in coarse prisms of M. P. 57-57.5 C. The yield is 65%. The l phenyl 3 chloro 5 dimethylamino py ridazone-(6) used as starting material can be prepared as follows:

'282 parts by weight of 1-phenyl-3-hydroxy-pyriadzone- ('6) are heated to gentle boiling while stirring in 1000 parts by volume of phosphorus oxychloride until dissolution is complete and hydrochloric acid is no longer evolved. 1000 parts byweight of phosphorus pentachloride are then added in five portions, and the whole is then heated again to the boil and refluxed for 12 hours. The reaction mass is then decomposed with a mhgture of ice and water while stirring, the temperaturebeing maintained below 50 C. by the. addition of ice. The reaction product is taken up in methylene chloride, the solution washed with water and sodium carbonate solution and dried. After distilling off the solvent the 1-phenyl-3,5-dichloro-pyridazone-( 6) is recrystallized from methanol. Its melting point it at 111-1 12 C.

48.2 parts by weight of l-phenyl-3,5'-dichloro-pyridazone-(6) dissolved in 100 parts by volume of absolute alcohol, are mixed with 250 parts by volume of 30% alcoholic dimethylamino solution while cooling. After the reaction has subsided, the mixture is heated for a further 2 hours in a sealed tube on the water-bath, the solvent is then distilled off, the residue taken up in methylene. chloride and washed with water. After distit ing: of the me h n blcr d i -phe vle hl r -fi ilrnethylamino,.r-pyridazonem ('61). is recrystallized fr0rn methauqt. Yellow-prisms of melting point 81 5-88.? C

are obtained. Yield: 84%..

Example 3 0.7 part by weight of potassium hydroxide and 2.31 parts by weight of 1-phenyl-3-hydroxy-4-dimethylaminopyridazone-(6) are dissolved in 40 parts by volume of methanol, the solution heated to the boil, and mixed drop se w t 2 Part y volume f; d tachr sa ine n 0 parts by volume of methanol. During the boiling, the

7 reaction mixture is kept alkaline by adding 2 N-potassium y rox d qcca i nal After hou the ntc h nq is distilled oil in vacuo, the residue mixed with 10 N-caustic soda solution, and extracted with methylene chloride. The organic solution is dried and evaporated and the residue recrystallized from a mixture of ether and petroleum ether. There is thus obtained the 1 -phenyl-3-methoxy- 4-dimethylamino-pyridazone-(6) described" in Example 1, melting at 100-101 C., in, a yield of 75%.

The 1 phenyl 3 hydroxy 4 dimethylamino py ridazone-() used as starting material can be. prepared as follows:

40 parts of 1-phenyl-3-hydroxy-4-chloro-pyridaz0ne- (6) described in Example 1 are heated at 155160 C. for 10 hours in a sealed bomb tube with 120 parts by volume of alcoholic 7 N-dimethylamine solution and 250 parts by volume of alcohol. The solution is then evaporated in vacuo, the residue dissolved in 2 N-caustic soda solution, the solution Washed with chloroform, filtered through animal charcoal, and finally acidified with 2 N-hydrochloric acid. The precipitate is filtered with suction and dried in vacuo at 60 C.' The yield is 69% and the melting point i 232-234 C. (decomposition).

Example 4 5 parts by weight of 1-phenyl-3-methoxy-5echlororpyridazone-(6j) are heated in a. closed tube for 4 hours to -100 C. with '10 parts. by volume of 3.0%. alcoholic dimethylamine solution and, 9.0 parts by volume of absolute alcohol. After distilling off the alcohol, the residue is dissolved in methylene chloride and the solution washed with water. The oil which remains after distilling off the methylene chloride crystallizes on scra hin h vfissel with a glass rod and. from its melting point. and. mixed melting point is found to be identical with the 1-phenyl-3- methoxy-5-dimethylamino-pyridazone-(6) described in Example 2. The yield is 86%.

The 1-phenyl-3-methoxy-S-chloro-pyridazone-(6) used as starting material can be prepared as follows:

11.1 parts by weight of 1--phenyl-3-hydroxy-5-chloropyridazone-(6) in parts by volume of methanol, are stirred with 5.3 parts by volume of dimethyl sulfate at 40 C. and a solution of 1.15 parts by Weight of sodium in 50 parts by volume of methanol is added dropwise. When the addition is complete the whole is ?oiled for 1 hour under reflux. After distilling oil the methanol under vacuum, the residue is taken up in methylene chloride and the methylene chloride solution washed With 2 N1- sodium carbonate solution for removal of unchanged starting material. After distilling off the methylene chloride, the residue is dissolved in hot isopropyl ether and the solution filtered hot with animal charcoal. It is then allowed to cool, filtered from separated by-product and the filtrate concentrated to. one-third of its volume. By scratching the wall of the flask, 1-phenyl-3-methoxy-5- chloropyridazone-(6) crystallizes in colorless prisms. After r c sta iza several t mes from. sopr y ethe the-productmelts at 8348.4' C The yield is. 24%- 7 What is claimed is:

1 Amino-pyridazone ,(6) compounds of the formula wherein R1 stands for a phenyl radical, R2 represents a lower alkoxy group and R3 an amino group substituted by at least one lower alkyl radical.

2. 1-phenyl-3-1ower alkoxy-M-lower dialkylaminopyridazone-(6), wherein M stands for one of the positions 4 and 5.

3. l-phenyl-3-lower alkoxy-4-lower dialkylamino-pyridazone-(6).

dazone- 6).

5. 1-phenyl-3-methoxy-4-dimethylamino pyrldazone- 6. 1-phenyl-3-methoxy-5-dirnethylamino pyridazone- No references cited. 

1. AMINO-PYRIDAZONE-(6) COMPOUNDS OF THE FORMULA 